The goal of this proposal is to identify and characterize T cell costimulatory pathways that prevent the induction of peripheral T cell anergy or cell death as a consequence of T cell antigen receptor (TCR) engagement. It is believed that under most circumstances TCR-mediated signal transduction serves primarily to activate a T cell to a state where the cell must make a further decision to proliferate and acquire effector function, be rendered anergic; or be induced to die by apoptosis. Which fate the cell chooses is determined by accessory or costimulatory signals received by the cell either at the same time as TCR engagement or shortly thereafter. One costimulatory pathway that plays a critical role in T cell fate is regulated by the CD28 receptor through interactions with its ligands B7-1 and B7-2 on antigen-presenting cells (APC). However, these same ligands can also engage CTLA-4, a CD28-related receptor, that has an inhibitory effect on peripheral T ell responses. The molecular mechanisms that result in CTLA-4's ability to inhibit T cell activation will be studied in the current proposal. In addition to CD28, several novel members of the TNF receptor family, CD30, OX-40, 4-1BB, have been identified as candidate costimulatory receptors on T cells and will be investigated for their role in T cells similar to that provided by CD40 to B cells. One important mechanism by which costimulation amplifies an immune response is through the enhancement of lymphocyte survival. Previous studies have demonstrated that both CD28 and CD40 can enhance lymphocyte survival through the ability to increase the expression of the cell survival gene bcl-x. These observations will be extended by investigating whether the survival function of Bcl-2 related proteins can also be regulated at the post- translational level by signal transduction initiated through costimulatory receptors and/or cytokine receptors. One of the important ways by which costimulatory receptors may enhance lymphocyte survival is through preventing post-translational inactivation of the anti-apopotic properties of either Bcl-2 and/or Bcl-x. By studying the molecular mechanisms through which CD28, CD30, OC-40, 4-1BB, and cytokine receptors enhance lymphocyte survival, we hope to learn more about the biochemical mechanisms that regulate lymphocyte survival during a peripheral immune response. Understanding the factors that regulate lymphocyte survival following an antigen encounter may play an important role in developing strategies to modulate peripheral T cell tolerance.